Virulence Differences of Monkeypox Virus Clades 1, 2a and 2b.1 in a Small Animal Model

Abstract

ABSTRACTHuman monkeypox, a disease with similarities to smallpox, is endemic in Africa where it has persisted as a zoonosis with limited human-to-human spread. Unexpectedly, the disease expanded globally in 2022 driven by human-to-human transmission outside of Africa. It is not yet known whether the latter is due solely to behavioral and environmental factors or whether the monkeypox virus is adapting to a new host. Genome sequencing has revealed differences between the current outbreak strains, classified as clade 2b, and the prior clade 2a and clade 1 viruses but whether these differences contribute to virulence or transmission has not been determined. We demonstrate that the wild-derived inbred CAST/EiJ mouse provides an exceptional animal model for investigating clade differences in monkeypox virus virulence and show that the order is clade 1 > clade 2a > clade 2b.1. The greatly reduced replication of the clade 2b.1 major outbreak strain in mice and absence of lethality at 100-times the lethal dose of a closely related clade 2a virus, despite similar multiplication in cell culture, suggest that clade 2b is evolving diminished virulence or adapting to other species.SIGNIFICANCEThree clades of monkeypox virus are recognized: clade 1 is present in the Congo Basin, causes 10% human mortality and is transmitted by rodents with little human-to-human spread; clade 2a exists in West Africa, has a low mortality and is also a zoonosis; clade 2b is currently spreading globally by human transmission. The genetic basis for differences in virulence and transmission have not been determined. A major roadblock is the need for a small animal model that can be studied under the stringent safety conditions required. Here we demonstrate that the three clades exhibit highly significant differences in CAST/EiJ mice in the order clade 1 > clade 2a > clade 2b, similar to the severity of clinical disease.